Progesterone is a naturally occurring steroid which is the main steroid secreted by women during their reproductive years. This steroid has been studied extensively and has been found to be a major precursor in the biosynthesis of most other steroids, particularly glucocortoids, androgens and estrogens. Progesterone also stimulates the growth of the uterus and a number of specific changes in the endometrium and myometrium. It is essential for the development of decidual tissue and the differentiation of luminal and glandular epithelial tissue. Progesterone also plays several roles in gestation, including breast enlargement, inhibition of uterine contractility, maintenance of gestation, immunological protection of the embryo, and inhibition of prostaglandin synthesis. Progesterone has been used pharmaceutically in the treatment of a number of clinical disorders such as luteal phase deficiency, dysfunctional uterine bleeding, endometriosis, endometrial carcinoma, benign breast disease, pre-eclampsia, and assisting in vitro fertilization, preventing early abortion and reducing the occurrence of endometrial hyperplasia in estrogen replacement therapy (ERT).
The most common progesteronal agents used are synthetic progesteronal agents which are accompanied by undesirable side effects such as depression and water retention. Additionally, many of the progestins derived from 19-nor-testosterone reverse the positive effects of estrogen on lipoprotein (HDL) levels. On the other hand, natural progesterone does not cause water retention, is rarely associated with depression and has no adverse effects upon lipid levels.
Breast cancer, a disease affecting primarily menopausal women, has been linked with progesterone and thus, the risks associated therewith should be reduced as much as possible during hormonal replacement therapy (HRT), i.e., the delivery of both estrogen and progesterone. Proliferation of the terminal duct lobular unit, from which most breast cancers arise, is relatively low during the follicular phase (estrogen alone) of the menstrual cycle. It is then increased by a factor of two in the mid-to-late luteal phase (estrogen and progesterone). Thus, the combination of estrogen and progesterone appears to have a greater stimulatory effect on cell division than estrogen alone, as compared to progesterone being an anti-mitotic agent in the endometrium. These observations have led to the development of the "estrogen-augmented by progesterone" hypothesis of breast cancer etiology. This hypothesis posits that breast cancer risk is increased by estrogen alone but is increased further by simultaneous exposure of the breast epithelium to estrogen and progesterone. Data from a prospective study in Sweden have suggested that risk associated with combination HRT is higher than any found for ERT alone, as the breast mitotic rate data would suggest.
Another problem which has been linked with progesterone is central nervous system (CNS) depression. Too much progesterone can lead to fatigue and progesterone has even been used as a anesthetic in certain cases.
Them have been many difficulties in administering natural progesterone at the appropriate serum and tissue levels to patients. When given orally, progesterone is rapidly metabolized. See e.g., Adlecruz, H. and Martin, F. J. Steroid Biochem., 13:231-244 (1980) and Maxson, W. S., and Hargrove, J. T., Fertil. Steril., 44:622-626 (1985). Some studies have shown that significant tissue progesterone concentration may be achieved with a 200 mg dose whereby serum levels were noted for six hours, but there was a wide inter-patient variance. Maxson, W. S. and Hargrove, J. T., Fertil. Steril., 44: 622-626 (1985); Whitehead, M. I., et al., Br. Med. J., 180:825-827 (1980); Sitruk-Ware, R., et all., Contraception 36:373-402 (1987).
Rectal administration of progesterone has also been attempted with 25 mg and 100 mg doses of progesterone which achieved peak plasma progesterone levels at 4 to 8 hours after administration followed by a gradual decline, but the maintenance of a stable plasma level has been difficult with this route. Maxson, W. S. Clinical Obstet. Gynecol., 30:465-477 (1987); Nillius, S. J. and Johansson, E. D. B. Am. J. Obstet. Gynecol., 110:470-479 (1971). Sublingual administration resulted in rapid appearance of progesterone in the serum reaching peak values of up to 10 times basal levels, but returning to basal levels within twenty-four hours. Villanueva, B., et al., Fertil. Steril,, 35:433-437 (1981). Nasal administration, using 20 mg and 30 mg doses, achieved mean maximum concentrations of 2.1 and 4.1 ng/ml, respectively, at approximately 30 and 240 minutes, respectively.
Intramuscular administration of progesterone has been attempted with 100 mg doses which achieved 40 to 50 ng/ml serum concentrations in two to eight hours. Nillius, S. J. and Johansson, E. D. B., Am, J, Obstet. Gynecol., 110:470-479 (1971). Such administration has shown that such injections need to be given every day or on alternate days to produce results. Whitehead, M., and Godfree, V. in Hormone Replacement Therapy, Churchill Livingston Edinburgh 1992, pp 91. Subdermal administration has also been assayed, with six 100 mg progesterone pellets being implanted in post-partum women. Croxatto, H. B., et al., Acta Endocrinol, 100: 630 (1982). Progesterone levels reached a peak of 4.4 ng/ml within the first week after insertion and reached a mean peak level of 1.9 ng/ml six months after implantation. Progesterone implants are not practical in cyclic therapy and moreover, physiological levels of progesterone are not achieved.
It has been demonstrated that topically applied radioactive progesterone can be absorbed through the skin. Mauvais-Jarvis, Progesterone., et al., J. Clin. Endocrinol. Metab., 29:1580-1587 (1969). Labelled metabolites were recovered in the urine at 48 hours after topical administration. However, the absorption was only 10% of the applied dose. The high fat solubility of progesterone is responsible for the prolonged retention of this steroid and the extensive local metabolism reduces the systemic effect of the steroid. It has been shown that treatment with topical application of progesterone to the breast produces no changes in the endometrial histology or break-through bleeding. Sitruk-Ware, R., et al., J. Clin. Endocrin. Metab., 44:771-774 (1977).
Progesterone has also been administered vaginally to postmenopausal women receiving ERT. Villanueva, B., et al., Fertil. Steril., 35:433-437 (1981). 50 mg/ml of progesterone in a suspension containing carboxymethyl cellulose and methylcellulose which was inserted into the vagina was characterized by a rapid absorption of the progesterone across the vaginal mucosa. There was an immediate appearance of the hormone in the peripheral circulation resulting in a 10-fold increase over the baseline serum levels (0.34 ng/ml) after 15 minutes. The peak levels were obtained 1 or 2 hours after administration and represented a 30-40-fold increase over baseline levels (12.25 ng/ml). The serum levels remained at this level over the next seven hours, declining over the next ten hours to 3.68 ng/ml. Villanueva, B., et at., Fertil. Steril., 35:433-437 (1981). These studies suggested that the absorption of progesterone was enhanced in women also undergoing ERT.
The vaginal administration of progesterone is complicated by a variability within and among patients. Side effects have included vaginal irritation and discharge, monilial vaginitis, pruritus and occasional delayed onset of menses. Maxson, W. S. Clinical Obstet. Gynecol., 30:465-477 (1987). However, no long term-side effects have been reported.